US2009203581A1PendingUtilityA1
Novel Peptides for Use in the Treatment of Obesity
Est. expiryJul 18, 2025(expired)· nominal 20-yr term from priority
Inventors:Ulrich SensfussLeif ChristensenJane SpetzlerKilian Waldemar Conde FrieboesHenning Thogersen
A61P 9/10A61P 35/00A61P 5/50A61P 9/12A61P 3/06A61P 3/10C07K 7/08A61K 47/545C07K 7/06C07K 14/685A61K 47/50A61P 19/02A61P 15/10A61K 47/542A61P 1/16
40
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Claims
Abstract
The present invention relates to novel peptide compounds which are effective in modulating one or more melanocortin receptor types, to the use of the compounds in therapy, to methods of treatment comprising administration of the compounds to patients in need thereof, and to the use of the compounds in the manufacture of medicaments. The compounds of the invention are of particular interest in relation to the treatment of obesity as well as a variety of diseases or conditions associated with obesity.
Claims
exact text as granted — not AI-modified1 . A compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain, branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen, hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues.
2 . The compound according to claim 1 , wherein T-A represents 10-(tetrazol-5-yl)decyl, 11-(tetrazol-5-yl)undecyl, 12-(tetrazol-5-yl)dodecyl, 13-(tetrazol-5-yl)tridecyl, 14-(tetrazol-5-yl)tetradecyl, 15-(tetrazol-5-yl)pentadecyl, 16-(tetrazol-5-yl)hexadecyl, 17-(tetrazol-5-yl)heptadecyl; 18-(tetrazol-5-yl)octadecyl or 19-(tetrazol-5-yl)nonadecyl.
3 . A compound according to formula II:
R 1 -R 2 —C(═O)—R 3 —S 1 -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - c [X 1 -X 2 -X 3 -Arg-X 4 -X 5 ]-R 4 [II]
wherein
R 1 represents tetrazol-5-yl or carboxy;
R 2 represents a straight-chain, branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen, hydroxy and aryl;
R 3 is absent or represents —NH—S(═O) 2 —(CH 2 ) 3-5 —C(═O)— or a peptide fragment comprising one or two amino acid residues and containing at least one carboxy group;
S 1 is absent or represents a 4-aminobutyric acid residue, Gly, β-Ala, or a glycolether-based structure according to one of the formulas IIIa-IIIg;
—HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —C(═O)— [IIIa]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —C(═O)] 2 — [IIIb]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —C(═O)] 3-5 — [IIIc]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —NH—C(═O)—CH 2 —CH 2 —CH 2 —C(═O)] 1-3 [IIId]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —NH—C(═O)—CH 2 —O—CH 2 —C(═O)] 1-3 [IIIe]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —C(═O)] 1-3 [IIIf]
—HN—CH 2 —CH 2 —[O—CH 2 —CH 2 ] 2-12 —O—CH 2 —C(═O)— [IIIg]
—HN—CH 2 —CH 2 —[O—CH 2 —CH 2 ] 4-12 —O—CH 2 —CH 2 —C(═O)— [IIIh]
Z 1 is absent or represents Gly, β-Ala, Ser, D-Ser, Thr, D-Thr, His, D-His, Asn, D-Asn, Gln, D-Gln, Glu, D-Glu, Asp, D-Asp, Ala, D-Ala, Pro, D-Pro, Hyp or D-Hyp;
Z 2 is absent or represents Gly, β-Ala, Ser, D-Ser, Thr, D-Thr, His, D-His, Asn, D-Asn, Gln, D-Gln, Glu, D-Glu, Asp, D-Asp, Ala, D-Ala, Pro, D-Pro, Hyp or D-Hyp;
Z 3 represents Ser, D-Ser, Thr, D-Thr, His, D-His, Asn, D-Asn, Gln, D-Gln, Glu, D-Glu, Asp, D-Asp, Ala, D-Ala, Pro, D-Pro, Hyp or D-Hyp;
Z 4 represents Gly, Ala, Pro, Hyp, Ser, homoSer, Thr, Tyr, Gln, Asn, 2-PyAla, 3-PyAla, 4-PyAla, His, homoArg, Arg, Lys, Dab, Dap or Om;
Z 5 represents Gly, Ala, Pro, Hyp, Ser, homoSer, Thr, Gln, Asn, 2-PyAla, 3-PyAla, 4-PyAla, His, homoArg, Arg, Lys, Dab, Dap or Orn;
Z 6 represents Ala, D-Ala, Val, D-Val, Leu, D-Leu, Ile, D-Ile, Met, D-Met, Nle or D-Nle;
X 1 represents Glu, Asp, Cys, homoCys, Lys, Om, Dab or Dap;
X represents His, Cit, Dab, Dap, Cgl, Cha, Val, Ile, tBuGly, Leu, Tyr, Glu, Ala, Nle, Met, Met(O), Met(O 2 ), Gln, Gln(alkyl), Gln(aryl), Asn, Asn(alkyl), Asn(aryl), Ser, Thr, Cys, Pro, Hyp, Tic, 2-PyAla, 3-PyAla, 4-PyAla, (2-thienyl)alanine, 3-(thienyl)alanine, (4-thiazolyl)Ala, (2-furyl)alanine, (3-furyl)alanine or Phe, wherein one or more hydrogens on the phenyl moiety of said Phe may optionally and independently be substituted by a substituent selected among halogen, hydroxy, alkoxy, nitro, benzoyl, methyl, trifluoromethyl, amino and cyano;
X 3 represents D-Phe, wherein one or more hydrogens on the phenyl moiety in D-Phe may optionally and independently be substituted by a substituent selected among halogen, hydroxy, alkoxy, nitro, methyl, trifluoromethyl and cyano;
X 4 represents Trp, 2-Nal, (3-benzo[b]thienyl)alanine or (S)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid;
X 5 represents Glu, Asp, Cys, homoCys, Lys, Om, Dab or Dap;
wherein X 1 and X 5 are joined, rendering the compound of formula II cyclic, either via a disulfide bridge deriving from X 1 and X 5 both independently being Cys or homoCys, or via an amide bond formed between a carboxylic acid in the side-chain of X 1 and an amino group in the side-chain of X 5 , or between a carboxylic acid in the side-chain of X 5 and an amino group in the side-chain of X 1 ;
R 4 represents OR′ or N(R′) 2 , wherein each R′ independently represents hydrogen or represents C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl which may optionally be substituted with one or more amino or hydroxy;
with the proviso that said compound of formula II is not 15-carboxypentadecanoyl-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2 or 2-[2-(15-carboxypentadecanoylamino)ethoxy]ethoxyacetyl-Ser-Gln-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2 ;
and pharmaceutically acceptable salts, prodrugs and solvates thereof.
4 . The compound according to claim 3 , wherein S 1 is absent.
5 . The compound according to claim 3 , wherein S 1 represents a structure according to formula IIIa.
6 . The compound according to claim 3 , wherein S 1 represents a structure according to formula IIIb.
7 . The compound according to claim 3 , wherein S 1 represents a structure according to formula IIIc.
8 . The compound according to claim 3 , wherein Z 1 is absent.
9 . The compound according to claim 3 , wherein Z 1 represents Gly.
10 . The compound according to claim 3 , wherein Z represents Ser, Thr, Gln, Gly or His.
11 . The compound according to claim 3 , wherein Z 2 represents Ser or Thr.
12 . The compound according to claim 3 , wherein Z 3 represents Gln, D-Gln, Asn, D-Asn, Ser or D-Ser.
13 . A compound according to formula IVa, IVb or IVc:
R 1 -R 2 —C(═O)—R 3 —S 2 -Z 4 -Z 5 -Z 6 - c [X 1 -X 2 -X 3 -Arg-X 4 -X 5 ]R 4 [IVa] R 1 -R 2 —C(═O)—R 3 —S 2 -Z 5 -Z 6 - c [X 1 -X 2 -X 3 -Arg-X 4 -X 5 ]R 4 [IVb] R 1 -R 2 —C(═O)—R 3 —S 2 -Z 6 - c [X 1 -X 2 -X 3 -Arg-X 4 -X 5 ]R 4 [IVc]
wherein
R 1 represents tetrazol-5-yl or carboxy;
R 2 represents a straight-chain, branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen, hydroxyl and aryl;
R 3 is absent or represents —NH—S(═O) 2 —(CH 2 ) 3-5 —C(═O)— or a peptide fragment comprising one or two amino acid residues and containing at least one carboxy group;
S 2 represents a glycolether-based structure according to one of the formulas IIIa-IIIIg;
—HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —C(═O)— [IIIa]
[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —C(═O)] 2 — [IIIb]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —C(═O)] 3-5 — [IIIc]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —NH—C(═O)—CH 2 —CH 2 —CH 2 —C(═O)] 1-3 — [IIId]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —NH—C(═O)—CH 2 —O—CH 2 —C(═O)] 1-3 — [IIIe]
—[HN—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —CH 2 —C(═O)] 1-3 — [IIIf]
—HN—CH 2 —CH 2 —[O—CH 2 —CH 2 ] 2-12 —O—CH 2 —C(═O)— [IIIg]
—HN—CH 2 —CH 2 —[O—CH 2 —CH 2 ] 4-12 —O—CH 2 —CH 2 —C(═O)— [IIIh]
Z 4 represents Gly, Ala, Pro, Hyp, Ser, homoSer, Thr, Tyr, Gln, Asn, 2-PyAla, 3-PyAla, 4-PyAla, His, homoArg, Arg, Lys, Dab, Dap or Om;
Z 5 represents Gly, Ala, Pro, Hyp, Ser, homoSer, Thr, Gln, Asn, 2-PyAla, 3-PyAla, 4-PyAla, His, homoArg, Arg, Lys, Dab, Dap or Orn;
Z 6 represents Ala, D-Ala, Val, D-Val, Leu, D-Leu, Ile, D-Ile, Met, D-Met, Nle or D-Nle;
X 1 represents Glu, Asp, Cys, homoCys, Lys, Orn, Dab or Dap;
X 2 represents His, Cit, Dab, Dap, Cgl, Cha, Val, Ile, tBuGly, Leu, Tyr, Glu, Ala, Nle, Met, Met(O), Met(O 2 ), Gln, Gln(alkyl), Gln(aryl), Asn, Asn(alkyl), Asn(aryl), Ser, Thr, Cys, Pro, Hyp, Tic, 2-PyAla, 3-PyAla, 4-PyAla, (2-thienyl)alanine, 3-(thienyl)alanine, (4-thiazolyl)Ala, (2-furyl)alanine, (3-furyl)alanine or Phe, wherein one or more hydrogens on the phenyl moiety of said Phe may optionally and independently be substituted by a substituent selected among halogen, hydroxy, alkoxy, nitro, benzoyl, methyl, trifluoromethyl, amino and cyano;
X 3 represents D-Phe, wherein one or more hydrogens on the phenyl moiety in D-Phe may optionally and independently be substituted by a substituent selected among halogen, hydroxy, alkoxy, nitro, methyl, trifluoromethyl and cyano;
X 4 represents Trp, 2-NaI, (3-benzo[b]thienyl)alanine or (S)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid;
X 5 represents Glu, Asp, Cys, homoCys, Lys, Om, Dab or Dap;
wherein X 1 and X 5 are joined, rendering the compound of formula IVa, IVb or IVc cyclic, either via a disulfide bridge deriving from X 1 and X 5 both independently being Cys or homoCys, or via an amide bond formed between a carboxylic acid in the sidechain of X 1 and an amino group in the side-chain of X 5 , or between a carboxylic acid in the side-chain of X 5 and an amino group in the side-chain of X 1 ;
R 4 represents OR′ or N(R′) 2 , wherein each R′ independently represents hydrogen or represents C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl which may optionally be substituted with one or more amino or hydroxy;
with the proviso that said compound of formula IVa, IVb or IVc is not 2-[2-(15-carboxypentadecanoylamino)ethoxy]ethoxyacetyl-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2 ;
and pharmaceutically acceptable salts, prodrugs and solvates thereof.
14 . The compound according to claim 13 , wherein S 2 represents a structure according to formula IIIa or IIIb.
15 . The compound according to claim 3 , wherein R 1 -R 2 represents 10-(tetrazol-5-yl)decyl, 11-(tetrazol-5-yl)undecyl, 12-(tetrazol-5-yl)dodecyl, 13-(tetrazol-5-yl)tridecyl, 14-(tetrazol-5-yl)tetradecyl, 15-(tetrazol-5-yl)pentadecyl, 16-(tetrazol-5-yl)hexadecyl, 17-(tetrazol-5-yl)heptadecyl; 18-(tetrazol-5-yl)octadecyl or 19-(tetrazol-5-yl)nonadecyl.
16 . The compound according to claim 3 , wherein R 1 -R 2 represents 13-(tetrazol-5-yl)tridecyl, 14-(tetrazol-5-yl)tetradecyl, 15-(tetrazol-5-yl)pentadecyl, 16-(tetrazol-5-yl)hexadecyl or 17-(tetrazol-5-yl)heptadecyl.
17 . The compound according to claim 3 , wherein R 1 -R 2 represents 15-(tetrazol-5-yl)pentadecyl.
18 . The compound according to claim 3 , wherein R 1 -R 2 represents 12-carboxydodecyl, 13-carboxytridecyl, 14-carboxytetradecyl, 15-carboxypentadecyl, 16-carboxyhexadecyl, 17-carboxyheptadecyl, 18-carboxyoctadecyl or 19-carboxynonadecyl.
19 . The compound according to claim 3 , wherein R 1 -R 2 represents
14-carboxytetradecyl.
20 . The compound according to claim 3 , wherein R 1 -R 2 represents
16-carboxyhexadecyl.
21 . The compound according to claim 3 , wherein R 3 is absent.
22 . The compound according to claim 3 , wherein R 3 represents
—NH—S(═O) 2 —(CH 2 ) 3-5 —C(═O)—, Glu, D-Glu, γ-Glu, D-γ-Glu, Asp, D-Asp, β-Asp, D-β-Asp or Gly-γ-Glu.
23 . The compound according to claim 3 , wherein R 3 represents
—NH—S(═O) 2 —(CH 2 ) 3 —C(═O)—.
24 . The compound according to claim 3 , wherein R 3 represents D-Glu, γ-Glu, β-Asp or Gly-γ-Glu.
25 . The compound according to claim 3 , wherein Z 4 represents Ser, homoSer, Gln, Asn, Tyr, His, Arg, homoArg, Lys, Orn, Dab or Dap.
26 . The compound according to claim 3 , wherein Z 4 represents Ser, His, Arg or Dap.
27 . The compound according to claim 3 , wherein Z 5 represents Ser, homoSer, Thr, Pro, Hyp, His, Lys, Om, Dab or Dap.
28 . The compound according to claim 3 , wherein Z 5 represents Ser, His or Dap.
29 . The compound according to claim 3 , wherein Z 6 represents Ala, Val, Leu, Ile, Met or Nle.
30 . The compound according to claim 3 , wherein Z 6 represents Nle.
31 . The compound according to claim 3 , wherein X 2 represents Ser, Hyp, Cit, Dap, Asn, Gln or (4-thiazolyl)Ala.
32 . The compound according to claim 3 , wherein X 2 represents Hyp, Dap, Cit or Gln.
33 . The A compound according to claim 3 , wherein X 2 represents Hyp.
34 . The compound according to claim 3 , wherein X 1 is Glu, X 3 is D-Phe, X 4 is Trp and X 5 is Lys.
35 . The compound according to claim 3 , wherein X 1 is Asp, X 3 is D-Phe, X 4 is Trp and X 5 is Lys.
36 . The compound according to claim 3 , wherein R 4 is NH 2 .
37 . The compound according to claim 3 , wherein R 4 is OH.
38 . The compound according to claim 3 , selected from the group consisting of:
16-(Tetrazol-5-yl)hexadecanoyl-Gly-Thr-Gln-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
16-(Tetrazol-5-yl)hexadecanoyl-Gly-Thr-Gln-Dap-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Thr-Gln-Dap-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Dap-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoyl-Gly-Ser-D-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]-ethoxy}acetyl-Nle-c[Glu-Dap-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoylamino]ethoxy}ethoxy)acetyl-His-Nle-c[Glu-Dap-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(15-Carboxypentadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}-acetyl-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(15-Carboxypentadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}-acetyl-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
the compound:
the compound:
the compound:
the compound:
the compound:
the compound
(2-{2-[2-(2-{2-[(R)-4-Carboxy-2-(16-(1H-tetrazol-5-yl)hexadecanoylamino)butanoylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl-Ser-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
the compound:
the compound:
{2-[2-(15-(Carboxy)pentadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
the compound:
the compound:
the compound:
15-Carboxypentadecanoyl-Gly-Ser-Ser-Tyr-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(15-Carboxypentadecanoylamino)ethoxy]ethoxy}acetyl-Ser-Tyr-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(15-Carboxypentadecanoylamino)ethoxy]ethoxy}acetyl-Asn-Asn-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 9
(2-{2-[(R)-4-Carboxy-2-(16-(tetrazol-5-yl)hexadecanoylamino)butanoylamino]ethoxy}-ethoxy)acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]-ethoxy}acetyl-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoylamino]ethoxy}ethoxy)acetyl-Arg-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-Dap-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoylamino]ethoxy}ethoxy)acetyl-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoylamino]ethoxy}ethoxy)acetyl-Gly-Ser-Gln-His-Dap-Nle-c [Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-D-Ser-His-His-Nle-c [Glu-Hyp-D-Phe-Arg-Trp-Lys]-OH
(2-[2-{(2-[2-{16-(Tetrazol-5-yl)hexadecanoylamino}ethoxy]ethoxy)acetylamino}ethoxy]-ethoxy)acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 9
(2-[2-{(2-[2-{(2-[2-{(2-[2-{16-(Tetrazol-5-yl)hexadecanoylamino}ethoxy]ethoxy)acetylamino}-ethoxy]ethoxy)acetylamino}ethoxy]ethoxy)acetylamino}ethoxy]ethoxy)acetyl-Gly-Ser-Gln-His-Dap-Nle-c [Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-His-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Nle-c [Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
4-(15-Carboxypentadecanoylsulfamoyl)butanoyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trn-Lys]-NH 2
(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butanoylamino]ethoxy}ethoxy)-acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
[2-(2-{(S)-4-Carboxy-4-[2-(17-carboxyheptadecanoylamino)acetylamino]butanoylamino}-ethoxy)ethoxy]acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[(S)-3-Carboxy-3-(17-carboxyheptadecanoylamino)propanoylamino]ethoxy}ethoxy)-acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Dab-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-homoSer-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Orn-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Lys-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Arg-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-2-PyAla-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-4-PyAla-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
39 . A method of delaying the progression from IGT to type 2 diabetes, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [II]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
40 . A method of delaying the progression from type 2 diabetes to insulin-requiring diabetes, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [II]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
41 . A method of treating obesity or preventing overweight, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
42 . A method of regulating appetite, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
43 . A method of inducing satiety, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
44 . A method of preventing weight gain after successfully having lost weight, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
45 . A method of increasing energy expenditure, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain, branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen, hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
46 . A method of treating a disease or state related to overweight or obesity, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
47 . A method of treating bulimia, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
48 . A method of treating a disease or state selected from atherosclerosis, hypertension, dia-betes, type 2 diabetes, impaired glucose tolerance (IGT), dyslipidemia, coronary heart dis-ease, gallbladder disease, gall stone, osteoarthritis, cancer, sexual dysfunction and risk of premature death, comprising administering to a patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen, hydroxy and aryl
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
49 . A method of treating, in an obese patient, a disease or state selected from type 2 diabetes, impaired glucose tolerance (IGT), dyslipidemia, coronary heart disease, gallbladder disease, gall stone, osteoarthritis, cancer, sexual dysfunction and risk of premature death, comprising administering to an obese patient in need thereof an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues, optionally in combination with one or more additional therapeutically active compounds.
50 . The method according to claim 39 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
51 . The method according to claim 39 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
52 . A method of activating MC4 in a subject, the method comprising administering to said subject an effective amount of a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain, branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen, hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues.
53 . The method according to claim 39 , wherein said compound is administered parenterally or sublingually.
54 . (canceled)
55 . A pharmaceutical composition comprising a compound according to formula I:
T-A-L-P [I]
wherein
T represents tetrazol-5-yl;
A represents a straight-chain branched and/or cyclic C 6-20 alkyl, C 6-20 alkenyl or C 6-20 alkynyl which may optionally be substituted with one or more substituents selected from halogen hydroxy and aryl;
L is a bond or a chemical structure covalently linking A and P; and
P represents a peptide structure comprising at least six α-amino acid residues.
56 . (canceled)
57 . The compound according to claim 13 , selected from the group consisting of:
16-(Tetrazol-5-yl)hexadecanoyl-Gly-Thr-Gln-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
16-(Tetrazol-5-yl)hexadecanoyl-Gly-Thr-Gln-Dap-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Thr-Gln-Dap-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Dap-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoyl-Gly-Ser-D-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]-ethoxy}acetyl-Nle-c [Glu-Dap-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoylamino]ethoxy}ethoxy)acetyl-His-Nle-c [Glu-Dap-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(15-Carboxypentadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}-acetyl-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(15-Carboxypentadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}-acetyl-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
the compound:
the compound:
the compound:
the compound:
the compound:
the compound:
(2-{2-[2-(2-{2-[(R)-4-Carboxy-2-(16-(1H-tetrazol-5-yl)hexadecanoylamino)butanoylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl-Ser-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
the compound:
the compound:
{2-[2-(15-(Carboxy)pentadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Dap-Nle-c [Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
the compound:
the compound:
the compound:
15-Carboxypentadecanoyl-Gly-Ser-Ser-Tyr-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(15-Carboxypentadecanoylamino)ethoxy]ethoxy}acetyl-Ser-Tyr-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 9
{2-[2-(15-Carboxypentadecanoylamino)ethoxy]ethoxy}acetyl-Asn-Asn-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[(R)-4-Carboxy-2-(16-(tetrazol-5-yl)hexadecanoylamino)butanoylamino]ethoxy}-ethoxy)acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]-ethoxy}acetyl-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoylamino]ethoxy}ethoxy)acetyl-Arg-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-Dap-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoylamino]ethoxy}ethoxy)acetyl-His-Dap-Nle-c [Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(2-{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoylamino]ethoxy}ethoxy)acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butanoyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-D-Ser-His-His-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-OH
(2-[2-{(2-[2-{16-(Tetrazol-5-yl)hexadecanoylamino}ethoxy]ethoxy)acetylamino}ethoxy]-ethoxy)acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-TrP-Lys]-NH 2
(2-[2-{(2-[2-{(2-[2-{(2-[2-{16-(Tetrazol-5-yl)hexadecanoylamino}ethoxy]ethoxy)acetylamino}-ethoxy]ethoxy)acetylamino}ethoxy]ethoxy)acetylamino}ethoxy]ethoxy)acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-HYP-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-His-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
4-(15-Carboxypentadecanoylsulfamoyl)butanoyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butanoylamino]ethoxy}ethoxy)-acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
[2-(2-{(S)-4-Carboxy-4-[2-(17-carboxyheptadecanoylamino)acetylamino]butanoylamino}-ethoxy)ethoxy]acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
(2-{2-[(S)-3-Carboxy-3-(17-carboxyheptadecanoylamino)propanoylamino]ethoxy}ethoxy)-acetyl-Gly-Ser-Gln-His-Dap-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Dab-Nle-c [Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-homoSer-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Orn-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Lys-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-Arg-Nle-c[Glu-HYP-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-2-PyAla-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
{2-[2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy]ethoxy}acetyl-Gly-Ser-Gln-His-4-PyAla-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2
58 . The method according to claim 40 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
59 . The method according to claim 40 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
60 . The method according to claim 40 , wherein said compound is administered parenterally or sublingually.
61 . The method according to claim 41 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
62 . The method according to claim 41 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
63 . The method according to claim 41 , wherein said compound is administered parenterally or sublingually.
64 . The method according to claim 42 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
65 . The method according to claim 42 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
66 . The method according to claim 42 , wherein said compound is administered parenterally or sublingually.
67 . The method according to claim 43 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
68 . The method according to claim 43 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
69 . The method according to claim 43 , wherein said compound is administered parenterally or sublingually.
70 . The method according to claim 44 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
71 . The method according to claim 44 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
72 . The method according to claim 44 , wherein said compound is administered parenterally or sublingually.
73 . The method according to claim 45 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
74 . The method according to claim 45 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
75 . The method according to claim 45 , wherein said compound is administered parenterally or sublingually.
76 . The method according to claim 46 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
77 . The method according to claim 46 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
78 . The method according to claim 46 , wherein said compound is administered parenterally or sublingually.
79 . The method according to claim 47 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
80 . The method according to claim 47 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
81 . The method according to claim 47 , wherein said compound is administered parenterally or sublingually.
82 . The method according to claim 48 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
83 . The method according to claim 48 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
84 . The method according to claim 48 , wherein said compound is administered parenterally or sublingually.
85 . The method according to claim 49 , wherein said additional therapeutically active compound is selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from, or associated with, diabetes.
86 . The method according to claim 49 , wherein said compound is administered to said patient in a unit dosage form comprising from about 0.05 mg to about 1000 mg of said compound.
87 . The method according to claim 49 , wherein said compound is administered parenterally or sublingually.Join the waitlist — get patent alerts
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